Genome-wide association (GWA) studies have made great progress in the identification of regions that are likely to contain genetic variants contributing to the risk of cardiovascular, lung and blood diseases. Despite these successes, variants identified through GWA studies appear to explain only a small fraction of the observed disease risk. This project addresses two needs of research - (1) the availability of large and well- characterized populations and (2) large-scale DNA sequencing. We propose to establish a multi-disciplinary Consortium among investigators of six well-phenotyped NHLBI cohorts - ARIC (Atherosclerosis Risk in Communities), CARDIA (Coronary Artery Risk Development in Young Adults), CHS (Cardiovascular Health Study), FHS (Framingham Heart Study), JHS (Jackson Heart Study), and MESA (Multi-Ethnic Study of Atherosclerosis). This Consortium provides over 40,000 participants with DNA and extensive phenotype information across the spectrum of cardiovascular, lung and blood disorders. The Consortium includes participants from four ethnicities (European, African, Hispanic and Asian) as well as families of European, African and Hispanic descent, useful for tracking transmission of rare variants and correlating them with phenotypes. A total of 30,517 Consortium DNA samples are immediately available for exome sequencing. There are many approaches to high throughput DNA sequencing and genotyping technologies. While decisions on sequencing, genotyping and analyses will be guided by the project Steering Committee, we propose to (a) sequence all exons in the human genome on participants from each of the six cohorts to enhance the ability to detect at least 80% (and up to 100%) of the variants with minor allele frequency greater than 0.1%;(b) conduct statistical genetic analyses on priority phenotypes to guide follow-up genotyping;(c) genotype all identified variants (~100,000) in the human exome in all eligible Consortium samples using data from the exome sequence, dbGaP and 1000 Genomes Project;and (d) continue to perform exome and whole genome sequencing on Consortium samples and conduct statistical genetic analysis to define the contributions of common and rare variants in the cohorts (individually and jointly through meta-analytic approaches) to phenotypes of cardiovascular, lung and blood diseases. Using a Working Group collaborative model, these data will be analyzed and disseminated across a broad spectrum of NHLBI phenotypes. This application represents a logical and highly innovative extension to research that has established the epidemiologic and genetic basis of disease over a range of ages in ethnically and geographically diverse populations. The proposed research will greatly advance our understanding of the genetic basis of disease and will provide a foundation for future functional studies. These data will be deposited for use by the greater scientific community and will be accessible through dbGaP. The project represents an extension of the research performed to date by the individual NHLBI-supported cohorts and will be possible only through this effort. PUBLIC HEALTH RELEVANCE: Cardiovascular, lung and blood disorders represent a complex, but interrelated, spectrum of conditions that arises from the action of multiple genetic and environmental risk factors. Although many regions of the genome have been identified that likely contain risk variants, few causal DNA changes have been identified. This research proposes to perform sequencing of coding regions across the human genome in order to identify or detect the potential causal changes that are associated with risk for cardiovascular, lung and blood diseases that may lead to better risk prediction, intervention and therapeutics (prevention).